scholarly journals Therapeutic advances in 5q-linked spinal muscular atrophy

2018 ◽  
Vol 76 (4) ◽  
pp. 265-272 ◽  
Author(s):  
Umbertina Conti Reed ◽  
Edmar Zanoteli
Keyword(s):  
Spinal Muscular Atrophy ◽  
Antisense Oligonucleotides ◽  
Viral Vector ◽  
Age Of Onset ◽  
Muscular Atrophy ◽  
Homozygous Mutation ◽  
Smn1 Gene ◽  
New Era ◽  
History Of ◽  
Smn Protein

ABSTRACT Spinal muscular atrophy (SMA) is a severe and clinically-heterogeneous motor neuron disease caused, in most cases, by a homozygous mutation in the SMN1 gene. Regarding the age of onset and motor involvement, at least four distinct clinical phenotypes have been recognized. This clinical variability is, in part, related to the SMN2 copy number. By now, only supportive therapies have been available. However, promising specific therapies are currently being developed based on different mechanisms to increase the level of SMN protein; in particular, intrathecal antisense oligonucleotides that prevent the skipping of exon 7 during SMN2 transcription, and intravenous SMN1 insertion using viral vector. These therapeutic perspectives open a new era in the natural history of the disease. In this review, we intend to discuss the most recent and promising therapeutic strategies, with special consideration to the pathogenesis of the disease and the mechanisms of action of such therapies.

scholarly journals Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy

2020 ◽  
Vol 4 (1) ◽  
pp. e202000889
Author(s):  
Anne Rietz ◽  
Kevin J Hodgetts ◽  
Hrvoje Lusic ◽  
Kevin M Quist ◽  
Erkan Y Osman ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Potential Drug ◽  
Transgenic Mouse Models ◽  
Fda Approval ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug–drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.

scholarly journals 3′ Splice Site Sequences of Spinal Muscular Atrophy Related SMN2 Pre-mRNA Include Enhancers for Nearby Exons

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Sunghee Cho ◽  
Heegyum Moon ◽  
Tiing Jen Loh ◽  
Hyun Kyung Oh ◽  
Hey-Ran Kim ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Splice Site ◽  
Genetic Disease ◽  
Muscular Atrophy ◽  
Cleavage Sites ◽  
Human Genetic Disease ◽  
Splice Site Selection ◽  
Smn1 Gene ◽  
Splice Site Sequence ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a human genetic disease which occurs because of the deletion or mutation of SMN1 gene. SMN1 gene encodes the SMN protein which plays a key role in spliceosome assembly. Although human patients contain SMN2, a duplicate of SMN1, splicing of SMN2 produces predominantly exon 7 skipped isoform. In order to understand the functions of splice site sequences on exon 7 and 8, we analyzed the effects of conserved splice site sequences on exon 7 skipping of SMN2 and SMN1 pre-mRNA. We show here that conserved 5′ splice site sequence of exon 7 promoted splicing of nearby exons and subsequently reduced splicing of distant exons. However, to our surprise, conserved 3′ splice site sequence of exon 7 and 8 did not promote splicing of nearby exons. By contrast, the mutation inhibited splicing of nearby exons and subsequently promoted splicing of distant exons. Our study shows that 3′ splice sites of exon 7 and 8 contain enhancer for their splice site selection, in addition to providing cleavage sites.

Onasemnogene Abeparvovec-xioi: Gene Therapy for Spinal Muscular Atrophy

2020 ◽  
Vol 54 (10) ◽  
pp. 1001-1009 ◽  
Author(s):  
Debra Stevens ◽  
Melanie K. Claborn ◽  
Brooke L. Gildon ◽  
Tiffany L. Kessler ◽  
Cheri Walker
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
English Language ◽  
Liver Toxicity ◽  
Muscular Atrophy ◽  
Data Extraction ◽  
Case Series ◽  
Survival Motor Neuron ◽  
Smn1 Gene ◽  
Smn Protein

Objective: To review the efficacy and safety of onasemnogene abeparvovec-xioi (Zolgensma) in the treatment of spinal muscular atrophy (SMA). Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to December 2019) was completed using the terms onasemnogene, AVXS-101, and spinal muscular atrophy. Manufacturer prescribing information, article bibliographies, and data from ClinicalTrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on ClinicalTrials.gov were incorporated in the reviewed data. Data Synthesis: Onasemnogene is the first agent for SMA utilizing gene therapy to directly provide survival motor neuron 1 ( SMN1) gene to produce SMN protein. Four publications of 1 clinical trial, 1 comparison study of treatment effects, and 1 combination therapy case series have been published. Relevance to Patient Care and Clinical Practice: Onasemnogene is a one time dose approved by the Food and Drug Administration for SMA patients <2 years old who possess mutations in both copies of the SMN1 gene. Conclusion: Onasemnogene appears to be an efficacious therapy for younger pediatric patients with SMA type 1. Concerns include drug cost and potential liver toxicity. Long-term benefits and risks have not been determined.

scholarly journals Metabolic Dysfunction in Spinal Muscular Atrophy

2021 ◽  
Vol 22 (11) ◽  
pp. 5913
Author(s):  
Marc-Olivier Deguise ◽  
Lucia Chehade ◽  
Rashmi Kothary
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Hormonal Regulation ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
Survival Motor Neuron ◽  
Potential Contribution ◽  
Metabolic Dysfunction ◽  
History Of ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.

scholarly journals The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy

2020 ◽  
Vol 15 ◽  
pp. 263310552097398
Author(s):  
Ravindra N Singh ◽  
Eric W Ottesen ◽  
Natalia N Singh
Keyword(s):  
Spinal Muscular Atrophy ◽  
Small Molecule ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Smn1 Gene ◽  
The Third ◽  
Splicing Silencer ◽  
Phenotypic Spectrum ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is 1 of the leading causes of infant mortality. SMA is mostly caused by low levels of Survival Motor Neuron (SMN) protein due to deletion of or mutation in the SMN1 gene. Its nearly identical copy, SMN2, fails to compensate for the loss of SMN1 due to predominant skipping of exon 7. Correction of SMN2 exon 7 splicing by an antisense oligonucleotide (ASO), nusinersen (Spinraza™), that targets the intronic splicing silencer N1 (ISS-N1) became the first approved therapy for SMA. Restoration of SMN levels using gene therapy was the next. Very recently, an orally deliverable small molecule, risdiplam (Evrysdi™), became the third approved therapy for SMA. Here we discuss how these therapies are positioned to meet the needs of the broad phenotypic spectrum of SMA patients.

scholarly journals Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development

2021 ◽  
Vol 22 (15) ◽  
pp. 7896
Author(s):  
Matthew E. R. Butchbach
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Smn1 Gene ◽  
Spinal Motor Neurons ◽  
Copy Numbers ◽  
Smn Protein ◽  
High Degree

Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1–SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.

scholarly journals Onasemnogene Abeparvovec (AVXS-101) for the Treatment of Spinal Muscular Atrophy

2021 ◽  
Vol 26 (5) ◽  
pp. 437-444
Author(s):  
Aimen Naveed ◽  
Hillary Calderon
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Clinical Studies ◽  
Viral Vector ◽  
Muscular Atrophy ◽  
Protein Deficiency ◽  
Smn2 Gene ◽  
Smn Gene ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a homozygous deletion in the survival motor neuron (SMN) gene on chromosome 5, resulting in a SMN protein deficiency. Small amounts of SMN protein are also produced by the SMN2 gene, which that differs from SMN1 by a single nucleotide. Spinal muscular atrophy types and phenotypic severity depend on the number of variations of the SMN2 gene and the amount of SMN2 protein produced. Because the SMN protein deficiency is the root cause of the disease, treatment strategies for SMA revolve around increasing SMN protein production. Nusinersen (Spinraza, Biogen, Cambridge, MA) was the only treatment option available for SMA until the FDA approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, Bannockburn, IL), a one-time–administered adeno-associated viral vector–based gene therapy that delivers the SMN gene to the motor neuron cells. Data from clinical studies show significant improvement in motor milestone achievements and ventilator-free survival but are limited by approximately 5 years' worth of results. This one-time intravenous injection of this new gene therapy also bears a hefty price tag; however, it may be more cost effective in the long run versus the multiple intrathecal administrations needed with nusinersen. Drug access and use are hindered by drug cost, payer reimbursement issues, and lack of long-term data from clinical studies. Questions also remain regarding the safety and efficacy of repeated drug administration for patients with advanced disease.

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